Influenza

Question 1

Viral release inhibitors

Answer 1

-Drugs: oseltamivir, zanamivir, peramivir
MOA: inhibit viral NA activity, then inhibit release of progeny influenza virus from infected host cells, halting spread of infection
Clinical use: A and B; avian (H5N1), and swine (H1N1)

Question 2

Oseltamivir route and side effects

Answer 2

Route: oral

Side effects: nausea, vomiting, headache, fatigue, diarrhea, neuropsychiatric events (self-injury, delirium - rare)

Question 3

Zanamivir route and side effects

Answer 3

Route: inhalation
Side effects: cough, bronchospasm, reversible decrease pulmonary function, transient nasal and throat discomfort
NOT FOR PATIENTS WITH UNDERLYING AIRWAY DISEASES

Question 4

Peramivir route and side effects

Answer 4

Route: IV

Side effects: diarrhea, skin or hypersensitivity reactions, delirium and abnormal behavior (rare)

Question 5

Viral replication inhibitors

Answer 5

Drug: Baloxavir marboxil
MOA: inhibits endonuclease activity of viral polymerase to prevent viral replication (RdRp contains PA site that contains the endonuclease active site and PB1 binding domain)
Side effects: diarrhea, bronchitis

Question 6

Viral uncoating inhibitors

Answer 6

Drugs: amantadine, rimantadine
MOA: inhibit viral uncoating by acting on M2 proteins so proton pumping can’t happen viral RNAs remain bound to the virus
Official use: influenza A (not used so much anymore due to mutations in M2 protein and resistance); Amantadine can be used in Parkinson’s
Side effects: GI and CNS (amantadine), birth defects

Question 7

Characteristics of flu virus

Answer 7

• (-) ssRNA
• orthomyxo-
• helical capsid
• enveloped
• 8 genome segments (segmented)
• 3 serotypes

Question 8

Life cycle of influenza

Answer 8

1. Attachment via sialic acid-HA binding
2. Receptor mediated endocytosis (encapsulated in endosome)
3. Membrane fusion and un-coating in endosomes activated by acidification (M2 protein)
4. Transcription of viral mRNAs (cap-snatching)
5. Replication in nucleus
6. Assembly and budding from plasma membrane - NA cleaves sialic acid to allow it to leave the cell

Question 9

Cap-snatching

Answer 9

Trans-splicing of 7 methylated guanosine caps from cell mRNAs

• grabs cap in nascent RNA strands and uses it to prime viral transcription
• polyadenylates after capping and viral mRNA is exported to cytoplasm through host pathways and translated by host machinery

Question 10

What does the endonuclease active site on the PA on the RdRp do?

Answer 10

Cleaves host mRNA to make RNA primers to initiate viral mRNA transcription catalyzed by RdRp

Question 11

Sialic acid preferentially bound by avian strains

Answer 11

Alpha 2,3

Question 12

Sialic acid preferentially bound by human strains

Answer 12

Alpha 2,6

Question 13

Where is alpha 2,3 in humans?

Answer 13

LRT

Question 14

Where is alpha 2,6 in humans?

Answer 14

URT

Question 15

Why is the avian flu hard to contract in humans?

Answer 15

Because the virus preferentially binds to alpha 2,3 which is in LRT in humans

Question 16

How are serotypes of flu decided?

Answer 16

HA and NA genes

Question 17

Antigenic drift

Answer 17

point mutation in glycoprotein causes antibodies to not recognize the site and prevents neutralization of the virus

Question 18

Antigenic shift

Answer 18

Co-infection of 2 viruses that recombine to make a new virus

Question 19

Major etiologies of secondary pneumonia in flu

Answer 19

S. pneumoniae, S. aureus, H. influenzae

Question 20

What are new host drug targets?

Answer 20

Sialic acid, HA

Question 21

What are new viral drug targets?

Answer 21

PB2, viral RNA, cap-dependent endonuclease, HA stem